City College of San Francisco Microbiology 12

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NOTE: INFORMATION ON THIS PAGE IS INTENDED FOR EDUCATIONAL USE ONLY. FOR MEDICAL ADVICE YOU SHOULD CONSULT WITH A PHYSICIAN

Introduction

The bacterium is named for the French researcher, Alexandre Yersin, who identified the organism in 1895 and for the disease that it produces "la peste" (known as the plague in English).

Perhaps no microbe strikes more fear into people than does the agent of the plague and for good reason. There have been three pandemics of bubonic plague which have been estimated to have cost 200 million lives: the first occurred in ancient Roman times (Justinian plague: 6th to 8th centuries), the Black Death (14th to 19th centuries) and modern plague (19th century to present day).The second pandemic was the most notable as the disease killed about one third of the population of Europe in the four year period between 1346 and 1350. At least 25 million Europeans died. During this period the disease was also referred to as the "Black death" because black blotches from subcutaneous hemorrhages appeared close to time of death. The disease spread rapidly in Europe from a combination of factors:

• The disease followed major trade routes and was quickly introduced into port cities
• A large rat population served as hosts for the flea vector of the disease
• Cities were crowded and many people lived in unsanitory conditions. Londoners mistakenly believed that they could avoid the disease by boarding themselves in their homes. Instead, the people created the crowded, unsanitary conditions favored for disease spread. As a result, half the population of London died.

Fear and ignorance of disease transmission favored the spread of the plague. Medical practices such as blood-letting, and the religious practice of flagellation created further sources of infection. Fear and ignorance also led to discrimination against people though to be to "blame" for the epidemic. Blamed with "poisoning drinking water,"entire Jewish communities were burned to the ground in 14th century Germany and Switzerland.

Many historians assert that the Black Death marked the end of the Middle Ages and that Europeans were forced to form new social and economic conditions.

Cultural and molecular characteristics

Y. pestis is an intracellular, nonmotile, gram-negative rod that belongs to the Enterobacteriaceae. It grows best at 28 C (body temperature of the flea vector) on blood agar or MacConkey agar (lactose nonfermenting). Stained rods are often described as "saftey pins" as the bacteria stain more densely at either end. The entire genome sequence of Y. pestis is now known and has revealed some interesting features (Parkhill et. al. Nature. Vol 413, 4 Oct. 2001). Notably, the organism has undergone large-scale genetic change and has acquired genes from other bacteria and viruses including ahesins, secretion systems and insecticidal toxins. Y. pestis is thought to have evolved from a clone of a gastrointestinal pathogen, Yersinia pseudotuberculosis, into a blood-borne pathogen that can also infect insects. Y. pestis carries three plasmids encoding various virulence factors (see below). Genome analysis has also revealed a large number of fimbriae-related genes which may play a role as adhesins.

Disease transmission and characteristics

Y. pestis has a complex life history. The organism has a predilection for rats and can be transmitted to humans by rat fleas following death of the rodent. For this reason, large scale rodent control always includes dual application of insecticides to prevent fleas from seeking human hosts. When a flea becomes infected by taking a blood meal, Y. pestis multiplies in and partially blocks the gut of the flea. As a consequence, the flea needs to feed more often and regurgitates bacteria into bite wounds. Bacteria in the bloodstream are carried to lymph nodes where they are taken up by macrophages. One plasmid codes for Yersinia outer membrane proteins (Yops), which collectively interfere with phagocytosis of the bacteria. Another plasmid codes for a capsule, which is produced at 37 C (body temperature of a mammalian host). After several days, an intense inflammatory reaction occurs in the lymph nodes which become remarkedly painful, swollen and necrotic. This form of the disease is called bubonic plague (an enlarged node is called a bubo). As the lymph nodes degenerate the bacteria may spill into the blood producing septicemic plague. Fever, septic shock and hemorrhaging under the skin develop rapidly. The skin literally begins to rot (gangrene) and the patient reeks of the odor of decay. This phenomenon gave the disease the name "Black Death." Secondary pneumonic plague develops in about 12% of patients with bubonic or septicemic plague. Bacteria that reach the lungs via the blood are coughed up in bloody sputum. This form of the disease is highly contagious and transmitted person-to-person. People who contract the disease by the aerosol route develop primary pneumonic plague.

Primary pneumonic plague resulting from the direct inhalation of bacilli rarely occurs in the USA. Two recent fatal cases were contracted after patients handled cats with pneumonic plague. It is the characteristics of pneumonic plague that make Y. pestis one of the most potentially effective and dreaded biological warfare agents. A biological attack using Y. pestis would probably cause an outbreak of primary pneumonic plague following inhalation of aerosolized bacteria. If not treated early the average time from exposure until death is 2-4 days.

Image Source: Nature. Vol 413, 4 October 2001.

Most cases of the disease in the USA involve a cycle known as sylvatic or rural plague. This form of the disease is maintained in wild rodents on every populated continent except Australia. In the Southwestern USA prairie dogs and ground squirrels are major hosts but domestic pets are potential hosts. Human cases have increased slightly in recent years as humans encroach into rural areas. Fortunately urban plague, maintained by city rats, does not occur in the USA.

Treatment

Limited data is available for the effective antibiotic therapy of plague. Historically the disease has been treated with streptomycin but only small supplies are available in the USA. Available evidence suggests treatment with doxycline, tetracyclines or ciprofloxacin may be effective if given early in the course of infection. If treatment of primary pneumonic plague is delayed beyond 24 hours of symptom onset, the likelihood of recovery is small.

Prevention

• Control of the disease primarily depends on controlling rodent reservoirs and the flea vectors.
• Disease surveillance should include awareness of the signs of primary pneumonic plague and ealry treatment following a biological attack
• The US-approved, formaldehyde-killed whole vaccine was discontinued in 1999 and is no longer available. The vaccine had efficay against bubonic but not primary pneumonic plague. Research is beeing conducted to develop a vaccine that protects against the latter condition.